A. Field of Invention
This invention is directed to in vivo treatment of neoplastic disease, including leukemia and solid tumors, through the sequential administration of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and 1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamide or pharmaceutically acceptable salts thereof.
B. Background Information
Although the arsenal of chemotherapeutic agents for treating neoplastic disease includes a number of clinically useful agents, control of cancer in warm blooded animals still remains a much sought after goal.
Cancer cells are characterized by high levels of inosine monophosphate dehydrogenase (IMP DH) activity. IMP DH is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis and therefore a sensitive target of chemotherapy. Weber, G., IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment, Adv. Exp. Med. Biol. 309B:287-292 (1991). 2-.beta.-D-ribofuranosylthiazole-4-carboxamide (tiazofurin), a synthetic C-nucleoside analogue, has been shown to selectively block IMP DH activity and deplete guanine nucleotide pools, thus forcing the cancer into remission. Weber, G., Critical Issues in Chemotherapy with Tiazofurin, Adv. Enzyme Regul. 29:75-95 (1989).
The mechanism behind the tiazofurin inhibition of IMP DH is well known. Tiazofurin is converted to its active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), and TAD inhibits the enzyme at the AND-NADH site of IMP DH. Yamada, Y. et al., IMP Dehydrogenase: Inhibition by the Antileukemic Drug, Tiazofurin, Leuk. Res. 13(2):179-184 (1989). The affinity of TAD to the enzyme is higher than that of the natural metabolite.
Ribavirin, although primarily utilized as a potent, broad-spectrum antiviral agent, also has been shown to inhibit IMP DH. Yamada, Y. et al., Action of the Active Metabolites of Tiazofurin and Ribavirin on Purified IMP Dehydrogenase, Biochem. 27:2193-2196 (1988). It proceeds under a different mechanism than tiazofurin, acting on a different site on the enzyme molecule. It is converted to its active metabolite, ribavirin-monophosphate (RMP), which inhibits the enzyme at the IMP-XMP site of IMP DH. As with tiazofurin, the affinity of its active form to the enzyme is higher than that of the natural metabolite.
When ribavirin is administered alone, it is less effective than tiazofurin at lower doses. (see FIGS. 1 and 2). In some cases it has exhibited little or no antitumor effect. Bekesi, J. G. et al., Treatment of Spontaneous Leukemia in AKR Mice with Chemotherapy, Immunotherapy, or Interferon, Cancer Research 36:631-639 (1976).
The National Cancer Institute (NCI) defines remission as a patient having a hematology of less than 5% blast cells in the bone marrow. This roughly corresponds with a IMP DH activity of less than 10% activity and a GTP level of less than 20%. Although tiazofurin has been tested in the treatment of cancer patients with positive results, researchers have not yet achieved lasting remission in patients or terminal differentiation of cancerous cells using the compound. Tricot et al., Tiazofurin: Biological Effects and Clinical Uses, Int'l J. Cell Clon. 8:161-170 (1990). Within 1 to 3 weeks after infusion with tiazofurin, the remission parameters return to the pre-infusion values. Thus, daily infusions of the compound are necessary.
Daily infusions of tiazofurin can lead to problems of toxic reaction or the development of resistance to the drug. Thus, in order to prolong the remission and keep the patient in the chronic phase, it has been recognized that tiazofurin may have to be administered in conjunction with a second compound. Weber, G., Critical Issues in Chemotherapy with Tiazofurin, Adv. Enzyme Reg., 29:75-95 (1989). Researchers have expended a great deal of effort to discover a compound which would have the necessary pharmacological properties to capitalize on the gains achieved by the administration of tiazofurin and to maintain patients in the chronic or remissive state. This process involves extensive research and testing to elucidate effectiveness, toxicity, and proper protocol.
The disclosed invention provides a method of attaining the advantages that have so far eluded researchers. It discloses a method of maintaining the consolidated gains of the tiazofurin-induced remission without the necessity of continual infusion of tiazofurin. As a result, the patient is relieved of the stress and expense of a long term hospital stay and the risks associated with the repeated infusions of tiazofurin. Instead, they can return home and enjoy life.
It provides a unique individualized treatment plan which minimizes side effects by tailoring the dosages to the patient's biochemical needs. Biochemical needs are carefully monitored using GTP concentration, IMP DH activity, and changes in blast cell counts. This allows for accurate fine-tuning of the patient's dose for the maintenance of the patient in the chronic phase with good quality of life.
In view of the inability of current cancer chemotherapeutics to successfully control all neoplastic disease, it is evident that there exists a need for new and additional cancer chemotherapeutic agents and methods of use.